The present invention relates to improved treatment of cancer in animals, including humans, by reducing the side effects of chemotherapy.
Cancers are a leading cause of death in animals and humans. The leading cancer therapies today are surgery, radiation and chemotherapy. In spite of advances in the field of cancer treatment, each of these known therapies has serious side effects. For example, surgery disfigures the patient or interferes with normal bodily functions. Chemotherapy or radiation therapies cause patients to experience acute debilitating symptoms including nausea, vomiting, diarrhea, hypersensitivity to light, hair loss, etc. The side effects of these cytotoxic compounds frequently limit the frequency and dosage at which they can be administered.
Chemotherapeutic agents have been found useful in treating cancer in humans. Broadly classified as antineoplastics, chemotherapeutic agents found to be of assistance in the suppression of tumors include but are not limited to alkyleting agents (e.g., nitrogen mustards), antimetabolites (e.G., pyrimidine analogs), radioactve isotopes (e.g., phosphorous and iodine), hormones (e.g., estrogens and adrenocorticosteroids), miscellaneous agents (e.g., substituted ureas) and natural products (e.g., vinca alkyloids and antibiotics). Although the preceding compounds are not curative agents, they are widely recognized in the medical profession as useful in the suppression, palliation, retardation and control of malignant tumors. While these compounds have been found to be effective and are in general clinical use as antiproliferative agents, there are well recognized drawbacks associated with their administration. The alkylating agents have marked cytotoxic action and the ability of these drugs to interfere with normal mitosis and cell division can be lethal. The antimetabolities can lead to anorexia, progressive weight loss, depression, and coma. Prolonged administration of antimetabolites can result in serious changes in bone marrow. Both the alkylating agents and the antimetabolities generally have a depressive effect on the immunosuppressive system. Prolonged administration of natural products such as vinca alkyloids can also result in bone marrow depression. Hydroxy urea and other chemically derived agents can lead to rapid reduction in levels of adrenocorticosteroids and their metabolites. The administration of hormonal compounds or radioactive isotopes is also undesireable from the viewpoint of inflicting damage on the immunosuppressive system and thereby disabling the body""s defenses against common infections. In most instances, it would be preferable to employ a chemotherapeutic agent which is effective in controlling, retarding, or suppressing the growth of malignant tumors while simultaneously acting to stimulate the patient""s immune system.
In accordance with the present invention, a method is provided in which the side effects of chemotherapy in cancer patients are reduced by administering thymosin xcex11 (xe2x80x9cTxcex11xe2x80x9d) in conjunction with the administration of the chemotherapy agent to the patient. The reduction in the severity of post-chemotherapy side effects increases the quality of life experienced by patients receiving chemotherapy.
It is known that the thymus produces a family of polypeptides termed thymosin and perhaps several other thymic hormones and/or factors which play an important role in the maturation, differentiation and function of T-cells. Thymosin has been found to induce T-cell differentiation and enhance immunological functions in genetically athymic mice, in adult thymectisized mice and in NZB mice with severe autoimmune reactions, in tumor bearing mice and in mice with casein-induced amyloidosis.
Thymosin xcex11, an acidic polypeptide isolated from thymosin fraction 5 is an immunomodulator that acts primarily by enhancing T-cell function and also has been shown to have direct anti-cancer effects. Thymosin xcex11 has been found to stimulate T-cell maturation, differentiation and function.
It has been previously documented that thymosin xcex11 reduces the incidence and severity of post-chemotherapy infections. It has now been found that the use of thymosin xcex11 in conjunction with the administration of antineoplastics (chemotherapeutic agents) significantly improves the cancer patient""s quality of life by reducing nausea, vomiting, loss of appetite, inability to sleep, decline in overall feeling, reduction in daily activity, fatigue and depression. The administration of thymosin xcex11 does not appear to result in any side effects.
The mechanism by which thymosin xcex11 acts to improve the patient quality of life is not yet known. Without being bound to any particular theory, one possibility may relate to the apparent ability of thymosin xcex11 to block neurotransmitter receptors. It is believed that most chemotherapeutic agents activate the chemoreceptor trigger zone (CTZ) and that the CTZ chemotherapy interaction triggers the release of neurotransmitters that activate the vomiting center. CTZ neurotransmitters that are thought to cause emesis include but are not limited to, dopamine, serotonin, histamine, norepinephrine, apomorphine, neurotensin, vasoactive intestinal polypeptide (VIP). In vitro studies, have shown that thymosin xcex11 has a VIP receptor binding effect. This may explain why thymosin xcex11 can control vomiting in patients whose vomiting could not be controlled by 5-HT blockers.
The increase in quality of life may be due to thymosin xcex11""s ability to control GI adverse effects like nausea and vomiting through the above described VIP receptor blocking effect or it could be the result of a reduction of low grade, clinically undetectable infections or some combination thereof.
In one embodiment of the present invention, the thymosin xcex11 is administered prior to the administration of the chemotherapy. The thymosin xcex11 may be administered on a single day or be administered on several days prior to the chemotherapy.
In another embodiment of the invention, the thymosin xcex11 is administered following the administration of the antineoplastic agent. In this embodiment, the thymosin xcex11 may be administered once or several times prior to the chemotherapy. This administration may take place on a single day or on a series of days prior to the administration of the antineoplastic agent.
In another embodiment of the invention, thymosin xcex11 is administered prior to and subsequent to the administration of the antineoplastic agent. This administration may take place on one or multiple days prior to and one or multiple days subsequent to the chemotherapy.
In one preferred embodiment, thymosin xcex11 is administered to cancer patients once each day on four days immediately preceding the administration of the antineoplastic agent and once on day 2 and on day 4 following chemotherapy.
Txcex11 can be administered in any suitable way, such as by injection, infusion, or transcutaneously. Other methods of administration may also be possible, such as orally as a liquid or solid dosage form. In preferred embodiments Txcex11 is injected.
Thymosin xcex11 may be administered at any suitable dosage level, e.g., within a range of about 0.1-3 mg. In preferred embodiments, thymosin xcex11 is administered via injection at a dosage of about 1.6 mg s.c.
Thymosin xcex11 can be administered to reduce side effects of any suitable antineoplastic agents, including one or more antineoplastic agent selected from the group consisting of alkylating agents (e.g., nitrogen mustards), antimetabolites (e.g., pyrimidine analogs), radioactive isotopes (e.g., phosphorous and iodine), hormones (e.g., estrogens and adrenocorticosteroids), miscellaneous agents (e.g., substituted ureas) and natural products (e.g., vinca alkyloids and antibiotics). Examples of such anitneoplastic agents include but are not limited to the following:
Adjunct Antineoplasic Therapy
Aloprim(trademark) for Injection
Anzemet(copyright) Injection
Anzemet(copyright) Tablets
Aredia(copyright) for Injection
Didronel(copyright) I.V. Infusion
Diflucan(copyright) Tablets, Injection, and Oral Suspension
Epogen(copyright) for Injection
Ergamisol(copyright) Tablets
Ethyol(copyright) for Injection
Kytril(copyright) Injection
Kytril(copyright) Tablets
Leucovorin Calcium for Injection
Leucovorin Calcium Tablets
Leukine(copyright)
Marinol(copyright) Capsules
Mesnex(copyright) Injection
Neupogen(copyright) for Injection
Procrit(copyright) for Injection
Salagen(copyright) Tablets
Sandostatin(copyright) Injection
Zinecard(copyright) for Injection
Zofran(copyright) Injection
Zofran(copyright) ODT(trademark) Orally Disintegrating Tablets
Zofran(copyright) Oral Solution
Zofran(copyright) Tablets
Zyloprim(copyright) Tablets
Alkylating Agents
Myleran(copyright) Tablets
Paraplatin(copyright) for Injection
Platinol(copyright) for Injection
Platinol-AQ(copyright) Injection
Thioplex(copyright) for Injection
Nitrogen Mustards
Alkeran(copyright) for Injection
Alkeran(copyright) Tablets
Cytoxan(copyright) for Injection
Cytoxan(copyright) Tablets
Ifex(copyright) for Injection
Leukeran(copyright) Tablets
Mustargen(copyright) for Injection
Nitrosoureas
BiCNU(copyright)
CeeNU(copyright)
Gliadel(copyright) Wafer
Zanosar(copyright) Sterile Powder
Antibiotics
Adriamycin(copyright) PFS/RDS for Injection
Blenoxane(copyright)
Cerubidine(copyright) for Injection
Cosmegen(copyright) for Injection
DaunoXome(copyright)
Doxil(copyright) Injection
Doxorubicin Hydrochloride for Injection, USP
Idamycin PFS Injection
Mithracin(copyright) for Intravenous Use
Mutamycin(copyright) for Injection
Nipent(copyright) for Injection
Novantrone(copyright) for Injection
Rubex(copyright) for Injection
Valstar(trademark) Sterile Solution for Intravesical Instillation
Antimetabolites
Cytosar-U(copyright) Sterile Powder
DepoCyt(trademark) Injection
Fludara(copyright) for Injection
Sterile FUDR
Leustatin(copyright) Injection
Methotrexate Sodium Tablets, Injection, for Injection
and LPF(copyright) Injection
Purinethol(copyright) Tablets
Thioguanine Tablets, Tabloid(copyright) Brand
Xeloda(copyright) Tablets
Hormonal Agonists/Antagonists
Androgens
Android(copyright) Capsules
Niladron(copyright) Tablets
Teslac(copyright) Tablets
Testred(copyright) Capsules
Antiandrogens
Casodex(copyright) Tablets
Eulexin(copyright) Capsules
Antiestrogens
Arimedex(copyright) Tablets
Fareston(copyright) Tablets
Femara(trademark) Tablets
Nolvadex(copyright) Tablets
Estrogen and Nitrogen Mustard Combination
Emcyt(copyright) Capsules
Estrogens
Estrace(copyright) Tablets
Estinyl(copyright) Tablets
Estratab(copyright) Tablets
Premarin(copyright) Tablets
Gonadotropin Releasing Hormone (GNRH) Analogues
Lupron(copyright) Depot
Lupron(copyright) Injection
Zoladex(copyright)
Progestins
Depo-Provera(copyright) Sterile Aqueous Suspension
Megace(copyright) Tablets
Immunomodulators
Ergamisol(copyright) Tablets
Proleukin(copyright) for Injection
Miscellaneous Antineoplastics
Camptosar(copyright) Injection
Celestone(copyright) Soluspan(copyright) Suspension
DTIC-Dome(copyright)
Elspar(copyright) for Injection
Etopophos(copyright) for Injection
Etoposide Injection
Gemzar(copyright) for Injection
Herceptin(copyright) I.V.
Hexalen(copyright) Capsules
Hycamtin(copyright) for Injection
Hydrea(copyright) Capsules
Hydroxyurea Capsules, USP
Intron(copyright) A for Injection
Lysodren(copyright) Tablets
Matulane(copyright) Capsules
Navelbine(copyright) Injection
Oncapsar(copyright)
Oncovin(copyright) Solution Vials and Hyporets
Ontak(trademark) Vials
Proleukin(copyright) for Injection
Rituxan(trademark) for Infusion
Rituxan(copyright) I.V.
Roferon(copyright)-A Injection
Taxol(copyright) Injection
Taxotere(copyright) for Injection Concentrate
TheraCys(copyright)
Tice(copyright) BCG Vaccine, USP
Velban(copyright) Vials
VePesid(copyright) Capsules
VePesid(copyright) for Injection
Vesanoid(copyright) Capsules
Vumon(copyright) for Injection
Photosensitizing Agents
Photofrin(copyright) for Injection
Skin and Mucus Membrane Agents
Efudex(copyright) Cream
Efudex(copyright) Topical Solution
Fluoroplex(copyright) Topical Cream
Fluoroplex(copyright) Topical Solution
The invention is illustrated by the following Example, which is not intended to be limiting.